JPS61246172A - Benzoxazinylmalonic acid derivative - Google Patents

Abstract

NEW MATERIAL:A dilower alkyl ester of (7, 8-difluoro-3-methyl-2, 3-dihydro-4 H-1, 4-benzoxazin-4-yl)m-ethylenemalonic acid. EXAMPLE:Diethyl (7, 8-difluoro-3-methyl-2, 3-dihydro-4H-1, 4-benzoxazin-4-yl) methylenemalonate. USE:An intermediate capable of producing ofloxacine (antimicrobial agent) in high yield. PREPARATION:A compound expressed by formula I is stirred in a solvent, e.g. (CH3)2SO2, in the presence of a strong base, e.g. KOH, at room temperature to give a compound expressed by formula II, which is then reacted with monochloroacetone in the presence of a catalytic amount of KI using a deacidifying agent, e.g. K2CO3, to afford a compound expressed by formula III. The resultant compound expressed by formula III is then catalytically reduced in the presence of a catalyst, e.g. Raney nickel, under ordinary pressure to give a compound expressed by formula IV, which is further reacted with diethyl dimethylaminomethylenemalonate while heating to afford the exemplified compound expressed by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides (7,8-difluoro-3-methyl-2,3-
Dihydro-48-1,4-benzoxazin-4-yl)methylenemalonic acid di-lower alkyl ester.

Ofloxacin (9-fluoro-3-methyl-10-(4-fluoro-3-methyl-10-(4-
Methyl-1-piperazico-7-oxo-2,3-dihydro 0-7H-pyrido [+, 2.3-del-1,4-
It is suitable for the production of benzoxazine (local acid).

The method for producing the compound of the present invention is as follows.

That is, when 2,3,4-trifluoronitrobenzene is stirred at room temperature in a solvent such as dimethyl sulfoxide or sulfolane in the presence of a strong base such as potassium hydroxide or sodium hydroxide, fluorine at the ortho position of the nitro group is dissolved. Atoms are selectively hydrolyzed to give 2,3-difluorotonitrophenol in good yield. 2. , 3-difluoro-6-nitronenol is reacted with monochlor 7cetone, and the resulting intermediate is catalytically reduced in the presence of a catalyst such as Raney nickel or palladium on charcoal at normal pressure to form an oxazine ring, 7
．． 8-difluoro-3-methyl-2,3-dihydro-4
H-1,4-benzione di>' is produced in good yield.

When this compound is heated as a free base or as an inorganic acid salt, such as a malate salt, with dimethylaminomethylenomalonic acid ester, the desired product (7,8-difluoro-3-methyl-2 ,3-dihydro-48-1,4
-benzoxazin-4-yl)methylene malonic acid ester is obtained.

When this compound is aged in polyphosphoric acid or its ester, a pyridine ring closure reaction occurs, and then treatment with an acid or base hydrolyzes the carboxylic acid nistyl and 8,10-difluoro-3-methyl-7 -oxo-2
,3-dihydrof H-pyrido[1,2゜3-del-
1,4-benzoxazine-local ponic acid is obtained,
When this product is heated and reacted with N-methylpiperazine, ofloxacin is obtained in high yield.

(JP-A-57-48F188 and JP-A-58-72
(See Publication No. 588).

Example 1 2.3.4- Dissolve 20 g of trifluoronitrobenzene in dimethyl sulfoxide 1001, dropwise add 20% potassium hydroxide aqueous solution 651 at 18 to 20°C, and stir at the same temperature for 5 hours. Add water 5001 to the reaction solution. Add chloroform and shake. The aqueous layer is separated, acidified with hydrochloric acid, and extracted with chloroform. After washing the extract with water and drying with Glauber's salt, chloroform was distilled off and 18.9 g of 2,3-difluoro-6-nitrophenol (85,5z
) was obtained.

Elemental analysis value Cb H3F2 Calculated value as NO3 C
41,18,H1,73,N 8.00 Analysis value C40
J5. H1,75,N 3.22 5.8g of the above compound
, monochloroacetone 5.0g, potassium carbonate 8.0g
and 0.8g of potassium iodide in 1ooIIll of acetone.
and reflux for 4 hours. Afterwards, insoluble materials are filtered off, the solvent is distilled off, and the residue is dissolved in benzene, washed with water, and then dried with Glauber's salt. The solvent was distilled off to give an oily product of 2-acetonyloxy-3,4-difluoronide a, 7 sen [i, 2 g (81
,0%) was obtained.

Elemental analysis value C9) 17 Calculated value as F2 Non C46,78, H3,05, N 8.08 Analysis value C
48,49,H2,9B, N 5.95 Compound 5 above
．． 0g was dissolved in ethanol 501, Raney nickel 51 was added thereto, and catalytic reduction was carried out at normal pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is distilled off. The residue was dissolved in benzene and shaken with 6z hydrochloric acid to precipitate 7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine hydrochloride, which was collected by filtration.

Melting point 182-185°C, 3.5 g (73,2:) - 2.0 g of the above hydrochloride and 2.5 g of diethyl dimethylaminomethylenemalonate were added to 20 ml of glacial acetic acid,
Stir at 90°C for 5 hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and the fraction eluted with benzene-chloroform (3:2) was obtained as an oil (
7,8-difluoro-3-methyl-2,3-dihydro-
2.4 g (74.8%) of diethyl 4H-1,4-benzoxazin-4-yl)methylenemalonate.

Elemental analysis value C+7HuF: Calculated value as NOs C
57, 48,! (5,39,N 3.94 analysis value C5
7,15,H5,35,N 3.9L2-acetonyloxy-3,4-difluoronitrobenzene 5.0g was dissolved in ethanol 50ff11, Raney 9 Nickel 51
and catalytic reduction at normal pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is distilled off. The residue is dissolved in benzene and shaken with loz hydrochloric acid. If a precipitate occurs, IO! Add hydrochloric acid. The aqueous layer is made alkaline with 101 aqueous sodium hydroxide solution and extracted with benzene. The benzene layer was washed with water and dried with Glauber's salt, and the solvent was distilled off to give 7,8-difluoro-3-methyl-2,3- as an oil.
Dihydro-4H-benzoxazine 2.58g (64%
) is obtained.

Add 0.80 g of the above compound and 0.80 g of diethyl dimethylaminomethylene malonate to 5 ml of glacial acetic acid,
Stir at ~30°C for 6 hours. The solvent was distilled off, the residue was purified by silica gel chromatography, and the fraction eluted with benzene-chloroform (3:2) was extracted as an oil (718-difluoro-3-methyl-2+3-dihydro-4H-1,4 -benzoxazin-4-yl)methylenediethylmalonate 0.78g (87,7riol?zReference example [7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzo Oxazin-4-yl] 2.0 g of diethyl methylenemalonate and 20 g of ethyl polyphosphate
The reaction mixture was stirred at 1.40-145°C for 1.5 hours, poured into ice water, and the precipitate was extracted with chloroform.

The extract was washed with a 5z potassium carbonate aqueous solution and then with water.
After drying the Glauber's salt, the solvent was distilled off to give 8,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4- having a melting point of 261°C. Benzoxazine-local ethyl ponate 1.30 g (74,
8%).

Claims (1)

[Claims] (7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylenemalonic acid dilower alkyl ester